2020 Fiscal Year Final Research Report
Generation of neo-self peptides in tumors
| Project Area | Creation, function and structure of neo-self |
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| Project/Area Number |
16H06498
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| Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kochi University |
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Principal Investigator |
UDAKA Keiko 高知大学, 教育研究部医療学系基礎医学部門, 教授 (40263066)
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| Co-Investigator(Kenkyū-buntansha) |
西村 泰治 熊本大学, 大学院生命科学研究部(医), 名誉教授 (10156119)
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| Project Period (FY) |
2016-06-30 – 2021-03-31
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| Keywords | HC分子 / ペプチド / 機械予測 / 腫瘍抗原 / T細胞 / 血管内皮細胞 / IL-6 / ペプチドワクチン |
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| Outline of Final Research Achievements |
Peptide immunotherapies against tumors exhibit limited tumor-regulatory activities. In this study, we found antigen presentation by tumor endothelial cells (ECs). Tumor ECs present tumor antigen peptides in the context of MHC class II molecules. Th cells which recognize tumor peptides infiltrate into tumor tissues in an antigen-specific manner. Th cells then induce infiltration of a large number of tumor-specific CTLs. A combined immunotherapy using HLA class I and class II-binding peptides exhibited potent tumor-regulatory activity. We, in collaboration with NEC, also developed a state-of the art platform to predict HLA-binding peptides which helps design peptide immunotherapies and identify peptides associated with autoimmune diseases. Finally, suppressive tumor microenvironment was investigated and IL6/soluble IL-6R complex secreted from tumor macrophages was found responsible for inducing upregulation of c-Maf in CD4 T cells thereby blocking differentiation into Th1 cells.
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| Free Research Field |
免疫学
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| Academic Significance and Societal Importance of the Research Achievements |
腫瘍特異的T細胞が少ないとICIによる腫瘍制御効果は期待できず、一方で、ICIは深刻な自己免疫反応を引き起こす。本研究では、腫瘍血管ECの抗原提示機能を利用して高い腫瘍制御効果を示す次世代ペプチド免疫療法を開発し、悪性腫瘍に治療の道を拓いた。また、機械学習を活用してHLA class I, class II分子結合性ペプチドを予測するplatformを開発し、任意の抗原に対してＴ細胞を誘導する技術、ペプチド反応性T細胞の誘導法や検出法を開発した。さらに免疫抑制環境を作るIL-6を介したTh1への分化阻害の機序を明らかにし、抗IL-6抗体併用療法の高い抗腫瘍活性を示した。
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